Reduced airway pH can be caused by exogenous as well as endogenous sources including airway inflammation, and can contribute to the pathophysiology of obstructive airway diseases. Neural mechanisms are known capable of mediating acidosis-induced bronchoconstriction, but whether reduced pH in the airway microenvironment has direct effects on airway smooth muscle (ASM) is unknown. We have discovered that ASM expresses OGR1, a member of a unique subfamily of G protein-coupled receptors (GPCRs) proposed to be proton-sensing. Preliminary data suggest OGR1 is expressed in ASM and, in response to reductions in extracellular pH, signals in a manner consistent with pro-contractile Gq-coupled GPCRs. Moreover, with modest step decreases in buffer pH that parallel the activation of OGR1, murine tracheal rings contract ex vivo, as do ASM cells from OGR1 +/+ but not -/- mice. Mindful of the inherent difficulties in investigating a receptor whose cognate ligand may be a proton, we have assembled a team of experts in GPCR biology, airway biology, and integrative models of acid-induced bronchoconstriction to undertake the challenge of: 1) establishing the relevance of OGR1 to ASM contractility; and 2) identifying therapeutic drugs and strategies to manipulate its signaling and function in ASM. In Aim 1, we propose to detail acid-induced signaling events in ASM, employing both genetic and molecular biology approaches on ASM cells to establish the contribution, and mechanism of activation, of OGR1. Aim 2 will validate recently discovered allosteric modulators as agonists/antagonists of OGR1 signaling, and take advantage of screening/drug discovery approaches and tools established for this PPG to identify means of antagonizing pro-contractile signaling while enhancing pro-relaxant signaling. In Aim 3, we will establish both relevance and robustness of pH- dependent OGR1 function in ASM by taking advantage of cutting edge models of cell, tissue, and airway contraction, and utilize drugs/strategies developed in Aim 2 to render OGR1 pro-relaxant as opposed pro- contractile. Collectively, these studies will help identify a novel signaling pathway in ASM that participates in the pathobiology of numerous airways diseases, and determine a means to target it therapeutically.